Project Summary This research proposal has been developed to equip the candidate, Dr. Jessica Hoffman, with the experience, skills, and tools needed to successfully transition into a faculty position at a large public research university. The proposed research will discover novel metabolic mechanisms that lead to small size and long life across natural genetic variation and lifespan extending interventions with a specific focus on the degradation of tryptophan to kynurenine. Dr. Hoffman will receive extensive training in mouse husbandry techniques, molecular biology, and metabolomics data acquisition and analysis under the guidance of her mentorship team, Drs. Steven Austad, Stephen Barnes, and Liou Sun, all at the University of Alabama at Birmingham and active members of UAB's Nathan Shock Center for Excellence in the Biology of Aging. Preliminary studies completed under the direction of Dr. Steven Austad indicate size plays a large role in explaining the variation in metabolomic profiles within a species (companion dogs) that show a negative correlation between body size and longevity. And work with Dr. Sun suggests that metabolomic profiles are different between small, long-lived growth hormone (GH) disrupted mice and wild type mice. One pathway found to be similar between the two species is the breakdown of tryptophan to kynurenine. In both small dogs and small GH disrupted mice kynurenine levels are higher and tryptophan levels are lower than their larger counterparts. This suggests that the degradation of tryptophan to kynurenine may be influencing the longevity extension seen in small individuals of a species. The overall goal of this project is to expand our knowledge of small size and long life and to further tease apart the molecular mechanisms that underlie the size longevity tradeoff seen across species. The overarching hypothesis is that tryptophan metabolic dysregulation is partially modulated by GH and energy intake and provides an IGF- I independent mechanisms of long-life and small body size across species. This hypothesis will be addressed by three specific aims, each of which will help develop Dr. Hoffman as an independent investigator. 1) Determine the dynamics of tryptophan metabolism to the longevity effect of reduced GH activity. 2) Determine how metabolomic profiles, specifically tryptophan degradation metabolism varies across different interventions that show smaller size and longer life across species. 3) Determine lifespan consequences of genetic manipulation of tryptophan metabolism genes in fruit flies. Overall, this proposal will increase our knowledge on the molecular underpinnings that lead to variation in body size and lifespan and will provide new hypotheses about potential interventions to improve lifespan and healthspan.